Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic process of the body:
1. Increased rate of protein synthesis in all cells of the body; PA1 2. Decreased rate of carbohydrate utilization in cells of the body; PA1 3. Increased mobilization of free fatty acids and use of fatty acids for energy. PA1 R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b, and R.sup.2b are independently hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.3 perfluoroalkoxy. --S(O).sub.m R.sup.7a, cyano, nitro, R.sup.7b O(CH.sub.2).sub.v -, R.sup.7b COO(CH.sub.2).sub.v -, R.sup.7b OCO(CH.sub.2).sub.v, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy; PA1 R.sup.7a and R.sup.7b are independently hydrogen, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, where the substituents are phenyl or substituted phenyl; phenyl or substituted phenyl where the phenyl substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy and v is 0 to 3; PA1 R.sup.3a and R.sup.3b are independently hydrogen, R.sup.9, C.sub.1 -C.sub.6 alkyl substituted with R.sup.9, phenyl substituted with R.sup.9 or phenoxy substituted with R.sup.9 ; ##STR3## R.sup.7b O(CH.sub.2).sub.v -, R.sup.7b COO(CH.sub.2).sub.v -, R.sup.7b OCO(CH.sub.2).sub.v -, R.sup.7b CO(CH.sub.2).sub.v -, R.sup.7b O(CH.sub.2).sub.v CO-, R.sup.4 R.sup.5 N(CH.sub.2).sub.v -, R.sup.7b CON(R.sup.4)(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NCO(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NCS(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NN(R.sup.5)CO(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NN(R.sup.5)CS(CH.sub.2).sub.v -, R.sup.7b CON(R.sup.4)N(R.sup.5)CO(CH.sub.2).sub.v -, R.sup.7b CON(R.sup.4)N(R.sup.5)CS(CH.sub.2).sub.v -, R.sup.4 N(OR.sup.7b)CO(CH.sub.2).sub.v - or R.sup.7a CON(OR.sup.7b)CO(CH.sub.2).sub.v -; PA1 R.sup.4, R.sup.4a, R.sup.5 are independently hydrogen, phenyl, substituted phenyl, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, substituted C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, or substituted C.sub.3 -C.sub.10 alkynyl where the substituents on the phenyl, alkyl, alkenyl or alkynyl are from 1 to 5 of hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, phenyl C.sub.1 -C.sub.3 alkoxy, fluoro, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, phenyl, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl, where the substituents on the phenyl are as defined above, C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl, or --NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, phenyl C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.5 -alkoxycarbonyl, or C.sub.1 -C.sub.5 -alkanoyl-C.sub.1 -C.sub.6 alkyl; or R.sup.4 and R.sup.5 can be taken together to form --(CH.sub.2).sub.r B(CH.sub.2).sub.s -- where B is CH.sub.2, O or S(O).sub.m or N--R.sup.10, r and s are independently 1 to 3 and R.sup.10 is as defined above; PA1 R.sup.6 is hydrogen, C.sub.1 -C.sub.10 alkyl, phenyl or phenyl C.sub.1 -C.sub.10 alkyl; PA1 A is ##STR4## where x and y are independently 0-3; R.sup.8 and R.sup.8a are independently hydrogen, C.sub.1 -C.sub.10 alkyl, trifluoromethyl, phenyl, substituted C.sub.1 -C.sub.10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, phenyl C.sub.1 -C.sub.3 alkoxy, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, phenyl, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl, PA1 C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl, or --NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are as defined above; or R.sup.8 and R.sup.8a can be taken together to form --(CH.sub.2).sub.t -where t is 2 to 6; and R.sup.8 and R.sup.8a can independently be joined to one or both of R.sup.4 and R.sup.5 to form alkyl bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts thereof. PA1 n is 0 or 1; PA1 p is 0 to 3; PA1 q is 0 to 2; PA1 w is 0 or 1; ##STR5## m is 0 to 2; R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b, and R.sup.2b are independently hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.3 perfluoroalkyl, --S(O).sub.m R.sup.7a, R.sup.7b O(CH.sub.2).sub.v -, R.sup.7b COO(CH.sub.2).sub.v -, R.sup.7b OCO(CH.sub.2).sub.v, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy; PA1 R.sup.7a and R.sup.7b are independently hydrogen, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, where the substituents are phenyl; phenyl and v is 0 to 2; PA1 R.sup.3a and R.sup.3b are independently hydrogen, R.sup.9, C.sub.1 -C.sub.6 alkyl substituted with R.sup.9, phenyl substituted with R.sup.9 or phenoxy substituted with R.sup.9 ; ##STR6## R.sup.7b O(CH.sub.2).sub.v -, R.sup.7b COO(CH.sub.2).sub.v -, R.sup.7b OCO(CH.sub.2).sub.v -, R.sup.7b CO(CH.sub.2).sub.v -, R.sup.4 R.sup.5 N(CH.sub.2).sub.v -, R.sup.7b CON(R.sup.4)(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NCO(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NCS(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NN(R.sup.5)CO(CH.sub.2).sub.v -, R.sup.7b CON(R.sup.4)N(R.sup.5)CO(CH.sub.2).sub.v -, R.sup.4 N(OR.sup.7b)CO(CH.sub.2).sub.v - or R.sup.7a CON(OR.sup.7b)CO(CH.sub.2).sub.v -; where v is as defined above; R.sup.4, R.sup.4a, R.sup.5 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, where the substituents on the alkyl are from 1 to 5 of hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, phenyl C.sub.1 -C.sub.3 alkoxy, fluoro, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, phenyl, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl, where the substituents on the phenyl are as defined above, C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy or formyl; PA1 R.sup.4 and R.sup.5 can be taken together to form --(CH.sub.2).sub.r B(CH.sub.2).sub.s -- where B is CH.sub.2, O or S(O).sub.m or N--R.sup.10 r and s are independently 1 to 3 and R.sup.10 is as defined above; PA1 R.sup.6 is hydrogen, C.sub.1 -C.sub.10 alkyl or phenyl C.sub.1 -C.sub.10 alkyl; PA1 A is ##STR7## where x and y are independently 0-2; R.sup.8 and R.sup.8a are independently hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1 -C.sub.6 alkoxy, phenyl, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl, or --NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.5 alkanoyl-C.sub.1 -C.sub.6 alkyl; or R.sup.8 and R.sup.8a can be taken together to form --(CH.sub.2).sub.t -where t is 2 to 4; and R.sup.8 and R.sup.8a can independently be joined to one or both of R.sup.4 and R.sup.5 to form alkyl bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts thereof. PA1 n is 0 or 1; PA1 p is 0 to 2; PA1 q is 0 to 2; PA1 w is 0 or 1; PA1 X is S(O).sub.m, --CH.dbd.CH--; PA1 m is 0 or 1; PA1 R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b, and R.sup.2b are independently hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.3 perfluoroalkyl, --S(O).sub.m R.sup.7a, R.sup.7b O(CH.sub.2).sub.v -, R.sup.7b COO(CH.sub.2).sub.v -, R.sup.7b OCO(CH.sub.2).sub.v, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy; PA1 R.sup.7a and R.sup.7b are independently hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, where the substituents are phenyl and v is 0 to 2; PA1 R.sup.3a and R.sup.3b are independently hydrogen, R.sup.9, C.sub.1 -C.sub.6 alkyl substituted with R.sup.9, phenyl substituted with R.sup.9 or phenoxy substituted with R.sup.9 ; ##STR8## R.sup.7b O(CH.sub.2).sub.v -, R.sup.7b COO(CH.sub.2).sub.v -, R.sup.7b OCO(CH.sub.2).sub.v -, R.sup.7b CO(CH.sub.2).sub.v -, R.sup.4 R.sup.5 N(CH.sub.2).sub.v -, R.sup.7b CON(R.sup.4)(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NCO(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NCS(CH.sub.2).sub.v -, R.sup.4 N(OR.sup.7b)CO(CH.sub.2).sub.v - or R.sup.7a CON(OR.sup.7b)CO(CH.sub.2).sub.v -; where v is as defined above; R.sup.4, R.sup.4a, R.sup.5 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, where the substituents on the alkyl are from 1 to 5 of hydroxy, C.sub.1 -C.sub.6 alkoxy, fluoro, phenyl, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl, where the substituents on the phenyl are as defined above, C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy; PA1 R.sup.6 is hydrogen, C.sub.1 -C.sub.10 alkyl; PA1 A is ##STR9## where x and y are independently 0-2; R.sup.8 and R.sup.8a are independently hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1 -C.sub.6 alkoxy, phenyl, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy; or R.sup.8 and R.sup.8a can be taken together to form --(CH.sub.2).sub.t -- where t is 2; and R.sup.8 and R.sup.8a can independently be joined to one or both of R.sup.4 and R.sup.5 to form alkyl bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; PA1 and pharmaceutically acceptable salts thereof. PA1 n is 0 or 1; PA1 p is 0 to 2; PA1 q is 1; PA1 w is 1; PA1 X is S(O).sub.m, --CH.dbd.CH--; PA1 m is 0 or 1; PA1 R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b, and R.sup.2b are independently hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.3 perfluoroalkyl, --S(O).sub.m R.sup.7a, R.sup.7b O(CH.sub.2).sub.v -, R.sup.7b COO(CH.sub.2).sub.v -, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy; PA1 R.sup.7a and R.sup.7b are independently hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, where the substituents are phenyl, phenyl and v is 0 or 1; PA1 R.sup.3a and R.sup.3b are independently hydrogen or R.sup.9 ; PA1 R.sup.9 is ##STR10## R.sup.7b O(CH.sub.2).sub.v -, R.sup.7b COO(CH.sub.2).sub.v -, R.sup.7b OCO(CH.sub.2).sub.v -, R.sup.7b CO(CH.sub.2).sub.v -, R.sup.4 R.sup.5 N(CH.sub.2).sub.v -, R.sup.7b CON(R.sup.4)(CH.sub.2).sub.v -, R.sup.4 R.sup.5 NCO(CH.sub.2).sub.v -, or R.sup.4 N(OR.sup.7b)CO(CH.sub.2).sub.v -; where v is as defined above; PA1 R.sup.4, R.sup.5 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, where the substituents on the alkyl are from 1 to 3 of hydroxy, C.sub.1 -C.sub.3 alkoxy, fluoro, phenyl, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl, where the substituents on the phenyl are as defined above; C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy; PA1 R.sup.4a is hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl where the substituents on the alkyl are from 1 to 3 of hydroxy; PA1 R.sup.6 is hydrogen; PA1 A is ##STR11## where x and y are independently 0-1; R.sup.8 and R.sup.8a are independently hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1 -C.sub.6 alkoxy, phenyl, R.sup.1 substituted or R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.5 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy; or R.sup.8 and R.sup.8a can be taken together to form --(CH.sub.2).sub.t -- where t is 2; and R.sup.8 and R.sup.8a can independently be joined to one or both of R.sup.4 and R.sup.5 to form alkyl bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; PA1 and pharmaceutically acceptable salts thereof.
A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,390. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. The instant compounds are non-peptidyl agents for promoting the release of growth hormone which may be administered parenterally, nasally or by the oral route.